12-14787465-G-T

Position:

• chr12-14787465-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_016312.3(WBP11):​c.1526C>A​(p.Pro509Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000585 in 1,368,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: WBP11 NM_016312.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.62

Genes affected

WBP11 (HGNC:16461): (WW domain binding protein 11) This gene encodes a nuclear protein, which colocalizes with mRNA splicing factors and intermediate filament-containing perinuclear networks. This protein has 95% amino acid sequence identity to the mouse Wbp11 protein. It contains two proline-rich regions that bind to the WW domain of Npw38, a nuclear protein, and thus this protein is also called Npw38-binding protein NpwBP. The Npw38-NpwBP complex may function as a component of an mRNA factory in the nucleus. [provided by RefSeq, Jul 2008]

C12orf60 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), WBP11. . Gene score misZ 2.9803 (greater than the threshold 3.09). Trascript score misZ 3.4119 (greater than threshold 3.09). GenCC has associacion of gene with vertebral, cardiac, tracheoesophageal, renal, and limb defects.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WBP11	NM_016312.3	c.1526C>A	p.Pro509Gln	missense_variant	12/12	ENST00000261167.7	NP_057396.1
C12orf60	XM_047428389.1	c.-517+1258G>T		intron_variant			XP_047284345.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WBP11	ENST00000261167.7	c.1526C>A	p.Pro509Gln	missense_variant	12/12	1	NM_016312.3	ENSP00000261167	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000585 AC: 8 AN: 1368508 Hom.: 0 Cov.: 31 AF XY: 0.00000448 AC XY: 3 AN XY: 670326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000750

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.1526C>A (p.P509Q) alteration is located in exon 12 (coding exon 11) of the WBP11 gene. This alteration results from a C to A substitution at nucleotide position 1526, causing the proline (P) at amino acid position 509 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.31		Loss of catalytic residue at P509 (P = 0.0404);
MVP		0.13
MPC		0.54
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1228025543; hg19: chr12-14940399;